Transcript Document

Recent Advances in
Antiretroviral Therapy
Hail M. Al-Abdely, MD
Consultant, Infectious Diseases
Rationale for Drug Combinations
CD4 + cell
NRTIs
Work here
NNRTIs
Work here
PIs
Work here
Development of AIDS is like an
impending train wreck
Viral Load = Speed of the train
CD4 count = Distance from cliff
HIV
infection
J. Coffin, XI International Conf. on AIDS, Vancouver, 1996
Viral Dynamics of HIV-1 Infection
Latently infected
CD4 lymphocytes
Productively infected
CD4 lymphocytes
<1%
T 1/2 ~1.6d
99%
Uninfected CD4
lymphocytes
2.6 days
per
generation
T1/2 ~5.7 hrs
HIV
<1%
Uninfected activated
CD4 lymphocytes
Long-lived cell
populations
Perelson et.al. Science 271:1582 (1996)
CD4 lymphocytes
infected with
defective virus
Viral dynamics




it takes 2.6 days to produce a new
generation of viral particles
estimated total HIV production is 10.3 x 109
virions per day
at least 99% of the virus pool is produced
by recently infected cells
retroviral therapy should be able to reduce
viral load within a few days
GOALS OF THERAPY
• Clinical goals: Prolongation of life and improved quality
of life
• Virologic goals: Reduction in viral load as much as
possible for as long as possible to: 1) halt disease
progression, and 2) prevent/reduce resistant variants
• Immunologic goals: Achieve immune reconstitution that
is quantitative (CD4 to normal range) and qualitative
(pathogen-specific immune response)
• Therapeutic goals: Rational sequencing of drugs in a
fashion that achieves virologic goals, but also: 1) maintains
therapeutic options; 2) is relatively free of side effects; and
3) is realistic in terms of probability of adherence
• Epidemiologic goals: Reduce HIV transmission
Antiretroviral Drugs Approved by FDA for HIV
Generic Name
Class
Firm
FDA Approval Date
zidovudine, AZT
NRTI
Glaxo Wellcome
March 87
didanosine, ddI
NRTI
Bristol Myers-Squibb
October 91
zalcitabine, ddC
NRTI
Hoffman-La Roche
June 92
stavudine, d4T
NRTI
Bristol Myers-Squibb
June 94
lamivudine, 3TC
NRTI
Glaxo Wellcome
November 95
saquinavir, SQV, hgc
PI
Hoffman-La Roche
December 95
ritonavir, RTV
PI
Abbott Laboratories
March 96
indinavir, IDV
PI
Merck & Co., Inc.
March 96
nevirapine, NVP
NNRTI
Boehringer Ingelheim
June 96
nelfinavir, NFV
PI
Agouron Pharmaceuticals
March 97
delavirdine, DLV
NNRTI
Pharmacia & Upjohn
April 97
zidovudine and lamivudine
NRTI
Glaxo Wellcome
September 97
saquinavir, SQV, sgc
PI
Hoffman-La Roche
November 97
efavirenz, EFV
NNRTI
DuPont Pharmaceuticals
September 98
abacavir, ABC
NRTI
Glaxo Wellcome
February 99
amprenavir
PI
Glaxo Wellcome
April 99
Deaths per 100,000 Population
Trends in Age-Adjusted* Rates of Death due to HIV Infection,
USA, 1982-1998
18
16
14
12
10
8
6
4
2
0
82
84
86
88
*Using the age distribution of the projected
year 2000 US population as the standard.
90
Year
92
94
96
**Preliminary 1998 data
98**
Good News
Highly active antiretroviral therapy has
Changed our view toward HIV from
inevitably fatal to a manageable disease
over several decades
Bad News
1.
2.
3.
4.
5.
Incomplete response
Complexity of treatment
Short and long term side effects
Cross resistance
Drug-drug interactions
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Cross resistance
5. Drug-drug interactions
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Cross resistance
5. Drug-drug interactions
Bad News
1. Incomplete response
2. Complexity of treatment
3. Short and long term side effects
4. Cross resistance
5. Drug-drug interactions
Bad News
1.
2.
3.
4.
Incomplete response
Complexity of treatment
Short and long term side effects
Cross resistance
5. Drug-drug interactions
Bad News
1. Incomplete response
•
•
2.
3.
4.
5.
Complete RNA suppression and sustained CD4
increase happens only in 60-80%.
Effectiveness is even lower in patients with high
replication rates and extensive antiretroviral
experience.
Complexity of treatment
Short and long term side effects
Cross resistance
Drug-drug interactions
Immunotherapy
Immunotherapy
• Directions
– Augmentation of specific immune response to
control viral replication.
– Preventive Vaccines.
Clues to immune control of HIV?
Subject JP:
Subject 161J:
Sx:
Dx:
Sx:
Dx:
F/U:
Fever, Rash, Headache
HIV ELISA Neg.
HIV RNA >700,000
Extensive Rx
AIDS at 11 mo.
Rapid CD4 cell decline
Viral Load >750,000
F/U:
Fever, Rash, Headache
HIV ELISA Neg.
HIV ELISA Pos.
No Rx
Well at 19 yrs.
CD4 1000
Viral Load < 500
Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4 cells
(Helper cells)
Generation of
HIV-1-specific killer cells
(CTL)
Loss of CTL function
due to inadequate HIV-1-specific
helper cells
Infection of
activated helper cells
Loss of HIV-1-specific helper
cells
Progression
T helper cells are the central
orchestrator of the immune system
CTL
Function
T helper cell
B Cell
Function
Antibody Production
NK Cell
Function
APC
Function
Cytokine production
Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4 cells
(Helper cells)
Antiviral
Rx
Generation of
HIV-1-specific killer cells
(CTL)
Maintenance of CTL function
due to adequate HIV-1-specific
helper cells
Nonprogression
Protection of activated
helper cells
Maintenance of HIV-1specific helper cells
HIV-1-specific T helper cells in individuals
treated during acute infection (n=7)
100
0 Months
2 Months
10
1
MB
JC
KM
ND
SJ
DK
KS
Barriers to the Development of an
Effective AIDS Vaccine
• Sequence variation
• Protective immunity in natural infection not clearly
established
• Desire to achieve sterilizing immunity
• Lack of adequate animal model to study vaccine protection
with HIV
• Latency and integration of HIV into host genome
• Transmission by cell-associated virus
• Limited knowledge about mucosal transmission and
immune responses
• Financial disincentives
• Ethical issues